An understanding of the serum responses of both HIV-1-infected individuals and vaccines is necessary for the development of an effective HIV-1 vaccine. Perhaps the most important biological aspect of a serum response is its neutralizing activity, with a close second being a compendium of its antigenic recognition. We will utilize the tools of structural and computational biology to develop probes to assist in the evaluation of the neutralizing activity of sera, and to decipher the HIV-1 elements recognized by both binding and neutralizing antibodies. Further, these probes will be used for the selection and isolation of B-cells so that their antibody gene loci can be sequenced, enabling the in-depth characterization of secreted antibodies. These capabilities are expected to enhance our understanding of how a broadly neutralizing antibody response develops during the course of infection and also of how the humoral immune system targets vulnerable regions on the HIV-1 Env glycoprotein. The tools of computational design allow for the manipulation of both the surface of a protein as well as its interior. Surface manipulation allows for a precise control of antigenicity, whereas interior manipulation allows for physical properties of flexibility and stability to be altered, thereby modulating surface antigencity. Together these tools should allow for a precise understanding of elicited serum responses. Such an understanding should facilitate the iterative structure-based improvement of immunogens.